The present invention relates to new quaternary ammonium compounds and to pharmaceutical compositions containing them.
The new quaternary ammonium compounds enable the vectorisation of active ingredients in cartilaginous tissue and hence the treatment of pathologies caused by attack on the cartilage whether they are articular or cancerous pathologies. They may also be used as diagnostic reagents, capable, for example, of revealing a pathology of the cartilage or a metabolism (radioactive marker, stained marker, . . . ).
The therapeutic agents currently available commercially for the treatment of articular pathologies, such as arthritis or osteoarthritis, generally exhibit a low affinity for the target tissues and require the administration of high doses to achieve the desired therapeutic effect.
The administration of such strong doses of active ingredients gives rise to an increase in the frequency of side effects. For example, the administration of non-steroidal anti-inflammatories is known to cause significant digestive toxicity.
In the field of bone cancerology, the therapeutic agents currently used for the treatment of chondrosarcomas are likewise known, for example, to produce undesirable side effects, especially toxicities, for example haematological or non-haematological toxicities.
Finally, in the field of diagnostic products for cartilaginous pathologies, the products currently used have the disadvantage of lacking specificity for the targets at which they are aimed.
There has thus been particular interest in functionalising those different kinds of compound in order specifically to target cartilaginous tissue and thus limit, or even suppress, the undesirable effects observed when such compounds are administered directly.
The new compounds forming the subject of the present invention make it possible, both by increasing the tropism and by decreasing the doses administered, for the side effects to be significantly attenuated and for the therapeutic index of the active molecules to be strengthened.
The present invention relates more specifically to compounds of a formula corresponding to formula (Ia) or (Ib): 
wherein:
M represents a molecule that can be used for the treatment or diagnosis of pathologies caused by attack on the cartilage,
R1, R2 and R3, which may be identical or different, represent a linear or branched (C1-C6)alkyl group, or R1, R2 and R3, together with the nitrogen atom carrying them, form a saturated or unsaturated nitrogen-containing heterocycle,
X represents a linear or branched (C1-C6)alkylene chain in which one or more xe2x80x94CH2-groups are optionally replaced by a sulphur atom, an oxygen atom, an xe2x80x94NRxe2x80x94 group (wherein R represents a linear or branched (C1-C6)alkyl group), a xe2x80x94COxe2x80x94 group, a xe2x80x94COxe2x80x94NHxe2x80x94 group, a xe2x80x94CO2xe2x80x94 group, an xe2x80x94SOxe2x80x94 group or an xe2x80x94SO2xe2x80x94 group,
n represents 0 or 1, and
Hal represents a halogen atom,
or, 
R4 represents a linear or branched (C1-C6)alkyl group,
Hal represents a halogen atom, and 
represents a molecule that can be used for the treatment or diagnosis of pathologies caused by attack on the cartilage, wherein the nitrogen atom may optionally be included in a saturated or unsaturated nitrogen-containing heterocyclic system, or included in a double bond.
Preferably, the compounds of formula (Ia) are compounds wherein:
n is 1,
X represents a linear or branched (C1-C6)alkylene chain, a group xe2x80x94NRxe2x80x94(CH2)mxe2x80x94 (wherein R is as defined hereinbefore), a group xe2x80x94COxe2x80x94(CH2)mxe2x80x94, or a group xe2x80x94COxe2x80x94NHxe2x80x94(CH2)m, in which groups m represents an integer from 1 to 5 inclusive.
R1, R2 and R3 in the compounds of formula (Ia) are preferably identical or different, linear or branched (C1-C6)alkyl groups or, together with the nitrogen atom carrying them, form a pyridine or piperidine ring (in which case one of those groups is a linear or branched (C1-C6)alkyl group).
The molecules M or 
that can be used for the treatment or the diagnosis of pathologies caused by attack on the cartilage are more especially: antiinflammatories, antiarthritics, antiosteoarthritics, analgesics or specific anti-tumour agents.
Preferred compounds of formula (Ia) used as active ingredient are:
molecules derived from tenidap of formula (Ia1): 
wherein:
X1 represents a linear or branched (C1-C6)alkylene group,
Rxe2x80x21, Rxe2x80x22 and Rxe2x80x23, which may be identical or different, represent a linear or branched (C1-C6)alkyl group, and
Hal represents a halogen atom,
molecules derived from melphalan of formula (Ia2): 
wherein:
X2 represents a group xe2x80x94NHxe2x80x94(CH2)mxe2x80x94 wherein m is as defined hereinbefore,
Rxe2x80x21, Rxe2x80x22 and Rxe2x80x23 are as defined hereinbefore, and
Hal represents a halogen atom,
molecules derived from chlorambucil of formula (Ia3); 
wherein:
X2, Rxe2x80x21, Rxe2x80x22 and Rxe2x80x23 are as defined hereinbefore, and
Hal represents a halogen atom,
molecules derived from glucosamine of formula (Ia4): 
wherein:
X4 represents a group xe2x80x94COxe2x80x94(CH2)mxe2x80x94 wherein m is as defined hereinbefore,
R1, R2 and R3 are as defined hereinbefore, and
Hal represents a halogen atom.
Preferred compounds of formula (Ib) used as active ingredient are:
molecules derived from piroxicam of formula (Ib1): 
wherein R4 and Hal are as defined hereinbefore,
molecules of formula (Ib2): 
wherein R4 and Hal are as defined hereinbefore.
Preferred compounds of formula (Ia) used as diagnostic reagents are compounds of formula (Ia5): 
wherein X1, R1, R2, R3 and Hal are as defined hereinbefore.
The invention relates also to a process for the preparation of the compounds of formula (Ia) or (Ib).
The compounds of formula (Ia) are obtained according to conventional processes of organic chemistry by functionalisation in one or more steps, according to the nature of the X group required, of a compound of formula Mxe2x80x94P (wherein M is as defined for formula (Ia) and P represents a hydrogen atom or a hydroxy group) or of a precursor of the compound of formula Mxe2x80x94P followed by the reactions necessary for the formation of the final compound of formula (Ia).
The compounds of formula (Ib) are obtained by reaction of an alkyl halide with a compound of formula 
as defined hereinbefore.
The molecules derived from tenidap of formula (Ia1) defined hereinbefore are obtained starting from 4-nitrophenyl 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxylate, which is reacted with an amine of formula (II): 
wherein X1, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
to yield a compound of formula (III): 
wherein X1, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which is subjected to the action of 2-thenoyl chloride in basic medium, under an inert atmosphere, and then to treatment with an acid,
to yield a compound of formula (IV): 
which is converted into the corresponding sodium salt,
which is then subjected to the action of a linear or branched (C1-C6)alkyl halide (Rxe2x80x23Hal) to yield a compound of formula (V): 
which, in hydrochloric medium, yields a compound of formula (Ia1), which if necessary is purified.
The molecules derived from melphalan of formula (Ia2) defined hereinbefore are obtained starting from melphalan, the amine function of which has been protected beforehand by a tert-butoxycarbonyl group (Boc), using an amine of formula (VI) in the presence of a peptide coupling reagent: 
wherein Rxe2x80x21, Rxe2x80x22 and m are as defined hereinbefore,
to yield a compound of (VII): 
wherein m, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which is subjected to the action of a linear or branched (C1-C6)alkyl halide, then to treatment with HCl,
to yield a compound of formula (Ia2), which if necessary is purified.
The molecules derived from chlorambucil of formula (Ia3) defined hereinbefore are obtained starting from chlorambucil, the acid function of which is converted into the corresponding acid chloride,
which is then reacted with an amine of formula (VI), in the presence or absence of a peptide coupling reagent: 
wherein Rxe2x80x21, Rxe2x80x22 and m are as defined hereinbefore,
a to yield a compound of formula (VIII): 
wherein m, Rxe2x80x21 and Rxe2x80x22 are as defined hereinbefore,
which is subjected to the action of a linear or branched (C1-C6)alkyl halide,
to yield a compound of formula (Ia2), which if necessary is purified.
The molecules derived from glucosamine of formula (Ia4) defined hereinbefore are obtained by reaction of glucosamine with an acid chloride of formula (IX):
Clxe2x80x94(CH2)mxe2x80x94COxe2x80x94Clxe2x80x83xe2x80x83(IX)
to yield a compound of formula (X): 
wherein m is as defined hereinbefore,
which is condensed with an amine of formula (XI): 
wherein R1, R2 and R3 are as defined hereinbefore,
to yield a compound of formula (Ia4), which if necessary is purified, and which is optionally separated into its isomers according to a conventional separation technique.
The molecules of formula (Ia5) defined hereinbefore are obtained starting from the compound of formula (XI): 
which is reacted with a haloalkylammonium halide of formula (XIII): 
wherein X1, R1, R2 and R3 are as defined hereinbefore, and Hal and Hal1, which may be identical or different, represent halogen atoms,
to yield a compound of formula (XIV): 
wherein X1, R1, R2, R3 and Hal are as defined hereinbefore,
which is reacted with sodium pertechneate in the presence of tin chloride,
to yield a compound of formula (Ia5), which if necessary is purified.
The molecules derived from piroxicam of formula (Ib1) defined hereinbefore are obtained starting from piroxicam, which is reacted with a linear or branched (C1-C6)alkyl halide, the resulting compound being purified if necessary.
The molecules of formula (Ib2) defined hereinbefore are obtained starting from the corresponding amine, which is reacted with a linear or branched (C1-C6)akyl halide, the resulting compound being purified if necessary.
In biological studies, the compounds of the present invention have demonstrated an increased tropism for cartilaginous tissues. Those molecules, functionised by the quaternary ammonium function, are furthermore distinguished by pharmaceutical behaviour very different from that of the non-functionalised molecules.
For example, a more elevated concentration has been observed in cartilage up to one hour after administration.
The invention extends also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) with one or more appropriate inert, non-toxic excipients. Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragxc3xa9s, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The useful dosage can be adapted in accordance with the nature and the severity of the disorder, the administration route and the age and weight of the patient and also varies in accordance with the nature of the compound used.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known products or products prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to customary spectroscopic techniques (infra-red NMR, mass spectrometry . . . ).